Heparin-farmeks

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Heparin-Pharmex (Heparin-Pharmex)

Composition:

Active substance: 1 ml of solution contains 5,000 IU of sodium heparin;

Excipients: benzyl alcohol, sodium chloride, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless or slightly yellowish solution.

Pharmacotherapeutic group.

Antithrombotic agents. Heparin group. ATC code B01AB01.

Pharmacological Properties.

Pharmacodynamics.

Heparin is a glycosaminoglycan (mucopolysaccharide) composed of sulfated residues of D-glucosamine and D-glucuronic acid.

Heparin is a direct-acting anticoagulant. In solution, heparin carries a negative charge, which promotes its interaction with proteins involved in the blood coagulation process. Heparin binds to antithrombin III (heparin cofactor) and inhibits blood coagulation by inactivating factors V, VII, IX, and X. As a result, factors that activate blood coagulation (kallikrein, IXa, Xa, XIa, XIIa) are neutralized, and the conversion of prothrombin to thrombin is disrupted. When thrombus formation has already begun, large amounts of heparin can inhibit further coagulation by inactivating thrombin and suppressing the transformation of fibrinogen into fibrin. Heparin also prevents the formation of stable fibrin clots by inhibiting the activation of fibrin-stabilizing factor. After parenteral administration, heparin delays blood coagulation, activates the fibrinolysis process, suppresses the activity of certain enzymes (hyaluronidase, phosphatase, trypsin), and reduces the effect of prostacyclin on platelet aggregation induced by adenosine diphosphate.

Pharmacokinetics.

After intravenous infusion, the maximum plasma concentration is reached within a few minutes; after slow intravenous infusion – no later than 2–3 minutes; after subcutaneous injection – within 40–60 minutes. The volume of distribution of heparin corresponds to the plasma volume and significantly increases with higher doses of the drug. Plasma proteins bind up to 95% of heparin at a concentration of 2 IU/mL of blood; at higher concentrations, binding is lower. Heparin is partially metabolized in the liver. Approximately 20% is excreted in urine in unchanged form and as uroheparin (which has 50% of the activity of the parent compound). The biological half-life ranges from 1.32 to 1.72 hours. The plasma elimination half-life is 30–60 minutes. Heparin accumulates in hepatic insufficiency. Heparin does not penetrate into breast milk and poorly crosses the placenta.

Clinical Characteristics.

Indications.

• For the prevention and treatment of thromboembolic diseases and their complications (acute coronary syndrome, thrombosis and embolism of major veins and arteries, cerebral and ocular vessels, phase I of disseminated intravascular coagulation syndrome, permanent form of atrial fibrillation with embolization);
• for prevention of postoperative venous thrombosis and pulmonary artery embolism (in low-dose regimen) in patients undergoing surgical procedures or in those who, for any other reasons, are at risk of developing thromboembolic disease;
• for prevention of blood coagulation during laboratory tests, dialysis, extracorporeal circulation, cardiac and vascular surgery, and direct blood transfusion.

Contraindications.

Hypersensitivity to heparin and/or benzyl alcohol; hemophilia; thrombocytopenia; hemorrhagic diatheses; suspected heparin-induced immune thrombocytopenia; peptic ulcer of the stomach and duodenum; severe arterial hypertension; liver cirrhosis associated with esophageal varices; severe renal and hepatic insufficiency; bacterial endocarditis; menstruation; recent surgical interventions, especially neurosurgical and ophthalmological procedures; ulcerative colitis; malignant neoplasms; hemorrhagic stroke (first 2–3 days); head injuries; retinopathy; hemorrhage into ocular tissues; destructive pulmonary tuberculosis; encephalomalacia; hemorrhagic pancreonecrosis; bleeding of any localization (open gastric ulcer, intracranial hemorrhage), except for hemorrhage occurring on the background of embolic pulmonary infarction (hemoptysis) or kidneys (hematuria); recurrent bleeding in history, regardless of localization; increased vascular permeability (e.g., in Werlhof's disease); shock state; threat of abortion.

Heparin must not be used in: patients who have consumed high doses of alcohol; via intramuscular injections; in acute and chronic leukemias; aplastic and hypoplastic anemias; acute cardiac or aortic aneurysm; during surgery on the brain or spinal cord, eyeball, or ears; after surgical procedures in areas where bleeding may be life-threatening; in diabetes mellitus; during epidural anesthesia in labor. Conductive anesthesia is contraindicated in patients receiving heparin therapeutically undergoing planned surgical procedures, as heparin use in rare cases may cause epidural or spinal hematomas, potentially leading to prolonged or irreversible paralysis.

Interaction with other medicinal products and other forms of interactions.

Oral anticoagulants (dicoumarin) and antiplatelet agents (acetylsalicylic acid, dipyridamole) should be discontinued at least 5 days before any surgical procedure, as they enhance the tendency to bleeding during or after surgery.

Direct and indirect-acting anticoagulants potentiate the effect of heparin. Concurrent use of ascorbic acid, antihistamines, digitalis preparations, tetracyclines, nicotine, nitroglycerin, corticotropin, and thyroxine may suppress the anticoagulant effect of the drug. Agents that reduce platelet aggregation (acetylsalicylic acid, dextrin, phenylbutazone, ibuprofen, metindol, dipyridamole, hydroxychloroquine, fibrinolytics, ascorbic acid, ergot alkaloids, indomethacin, sulfinpyrazone, probenecid, cephalosporins, ketorolac, epoprostenol, clopidogrel, ticlopidine, streptokinase, intravenous penicillins, ethacrynic acid, cytostatics), when used concurrently with heparin, may cause hemorrhage and therefore must be used with extreme caution. The risk of bleeding is also increased during combined therapy with heparin and ulcerogenic, immunosuppressive, and thrombolytic agents.

Heparin may displace phenytoin, quinidine, propranolol, benzodiazepines, and bilirubin from plasma protein binding sites. Concurrent use of alkaline medicinal products, enalaprilat, and tricyclic antidepressants may lead to binding with heparin, resulting in mutual reduction of efficacy.

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II antagonists: hyperkalemia may develop.

Alcohol: concurrent consumption of alcoholic beverages significantly increases the risk of bleeding.

The risk is also increased when Heparin-Farmeks is used concurrently with ulcerogenic, immunosuppressive, and thrombolytic medicinal products.

Effect on laboratory test results. False elevation of total thyroxine and triiodothyronine levels. Pseudometabolic acidosis and hypocalcemia (in patients undergoing hemodialysis). Inhibition of chromogenic limulus tests for endotoxin detection. Heparin may interfere with the measurement of aminoglycosides by immunoassay.

Special precautions.

When prescribing heparin for therapeutic purposes, the drug must not be administered intramuscularly. Biopsies, epidural anesthesia, and diagnostic lumbar punctures should be avoided.

Use with caution in patients who have previously experienced hypersensitivity reactions to low-molecular-weight heparins.

Platelet count should be determined before initiating treatment, on the first day of therapy, and every 3–4 days throughout the entire period of heparin use, especially between days 6 and 14 after the start of treatment. A sudden drop in platelet count requires immediate discontinuation of the drug and further investigation to determine the etiology of thrombocytopenia. If heparin-induced thrombocytopenia type I or II is suspected, heparin therapy should be discontinued.

Except for low-dose regimens, coagulation tests should always be performed before initiating therapy.

Heparin should be administered with extreme caution in patients with conditions that increase the risk of bleeding (e.g., arterial hypertension).

When switching from heparin therapy to oral anticoagulants, heparin may be discontinued only when the indirect anticoagulants have achieved a therapeutic prolongation of prothrombin time for at least 2 consecutive days.

To prevent significant hypocoagulation, the heparin dose should be reduced without increasing the intervals between injections.

During heparin therapy, hematological parameters should be monitored, and the patient's clinical condition and the development of hemorrhagic complications should be closely observed.

In patients aged 60 years and older, heparin may cause hemorrhagic events, especially in women and in patients with impaired renal function.

Patients sensitive to animal-derived proteins may also be sensitive to heparin.

If hypersensitivity is suspected, a diluted test dose of 1000 IU should be slowly administered intravenously several minutes before administering the full dose.

The use of the medicinal product Heparin-Farmeks requires special caution during the postoperative and postpartum periods within the first 3–8 days (except for vascular surgery and cases where heparinization is indicated for life-threatening conditions).

Particular caution is required during the first 36 hours after delivery.

In patients with arterial hypertension, blood pressure should be monitored.

In patients with diabetes mellitus, renal insufficiency, metabolic acidosis, elevated blood potassium levels, or those receiving potassium supplements, serum potassium levels should be continuously monitored during heparin therapy due to the increased risk of hyperkalemia.

Use during pregnancy or breastfeeding.

Heparin is not contraindicated during pregnancy. The drug does not cross the placenta. Although heparin does not pass into breast milk, its use in nursing mothers has in isolated cases been associated with rapid (within 2–4 weeks) development of osteoporosis and spinal damage. The decision to use the drug should be made individually, weighing the benefit to the mother against the potential risk to the fetus.

Ability to affect reaction speed when driving or operating machinery.

There are no data regarding the effect of heparin on the ability to drive or operate machinery.

Administration and Dosage.

Heparin-Farmeks is administered as intravenous bolus or intermittent injections, or subcutaneously. Before administration of the drug, blood clotting time, thrombin time, activated partial thromboplastin time (aPTT), and platelet count should be determined. Heparin should be diluted only with 0.9% sodium chloride solution.

Adults: For acute thrombosis, treatment is initiated with intravenous administration of 10,000–15,000 IU of Heparin-Farmeks, with monitoring of venous blood clotting time, thrombin time, and activated partial thromboplastin time. Subsequently, 5,000–10,000 IU of Heparin-Farmeks are administered intravenously every 4–6 hours. The adequate dose of Heparin-Farmeks is considered to be one that prolongs blood clotting time by 2.5–3 times and activated partial thromboplastin time by 1.5–2 times.

For prevention of acute thrombosis, Heparin-Farmeks is administered subcutaneously at 5,000 IU every 6–8 hours. In the first phase of disseminated intravascular coagulation (DIC) in adults, heparin is administered subcutaneously for a prolonged period at a daily dose of 2,500–5,000 IU, with monitoring of thrombin time. The daily dose is gradually reduced 1–2 days before discontinuation of Heparin-Farmeks.

During open-heart surgery with extracorporeal circulation apparatus, patients receive Heparin-Farmeks at an initial dose of not less than 150 IU per 1 kg of body weight. If the procedure lasts less than 60 minutes, a dose of 300 IU/kg is administered; if longer than 60 minutes, a dose of 400 IU/kg is administered.

For prophylactic purposes, Heparin-Farmeks is administered subcutaneously at a dose of 5,000 IU 2 hours before surgery, followed by 5,000 IU every 6–8 hours for 7 days.

As an adjunct to streptokinase, Heparin-Farmeks at 5,000 IU three times daily or 10,000–12,500 IU twice daily is indicated in patients at high risk of thromboembolic complications:

• in recurrent myocardial infarction;
• in persistent atrial fibrillation with embolization.

In acute coronary syndrome (unstable angina or myocardial infarction), 5,000 IU of Heparin-Farmeks is initially administered as an intravenous bolus, followed by continuous intravenous infusion at a rate of 1,000 IU/hour. The infusion rate should be adjusted to maintain activated partial thromboplastin time (aPTT) at 1.5–2 times the normal value during the first 2–3 days.

Children: Heparin-Farmeks is administered according to the following regimen: initial dose is 50 IU/kg (intravenous injection/infusion), maintenance dose is 100 IU/kg every 4 hours. The average daily dose in children is 300 IU/kg.

In infants, doses of 2–10 IU/kg/hour are administered intravenously (continuously or intermittently). Subcutaneous administration in infants is at a daily dose of 200–300 IU/kg, divided into 4–6 injections.

In all cases, indirect anticoagulants should be prescribed 1–3 days before discontinuation of Heparin-Farmeks.

Children.

Doses in children should be adjusted according to body weight. Do not use in premature infants or newborns, as the preparation contains benzyl alcohol. Allergic reactions, including toxic ones, are possible in children under 3 years of age.

Overdose.

In case of overdose, bleeding may occur. In cases of minor bleeding, reducing the dose or temporarily discontinuing the drug may be sufficient. In cases of severe bleeding, heparin administration should be urgently discontinued and the antidote, 1% protamine sulfate solution (administered slowly intravenously), should be given. The dose is calculated so that 1 mg of protamine sulfate neutralizes 85 IU of heparin.

Adverse Reactions

The most common adverse reactions include hemorrhages, elevated liver enzymes, reversible thrombocytopenia, and various dermatological disorders. Isolated cases of generalized allergic reactions, skin necrosis, and priapism have also been reported.

Blood system: Type I and type II thrombocytopenia, epidural and spinal hematomas.

Psychiatric disorders: Depression.

Nervous system: Headache.

Gastrointestinal tract: Nausea, vomiting, diarrhea.

Hepatobiliary system: Increased levels of liver transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), lactate dehydrogenase, gamma-glutamyl transferase, and hyperlipidemia (these disorders are reversible and resolve upon discontinuation of the drug).

Skin and subcutaneous tissue: Skin rashes (erythematous, maculopapular), urticaria, pruritus, burning and itching of the skin of the feet, skin necrosis, erythema multiforme, alopecia.

Musculoskeletal system: Osteoporosis, bone demineralization.

Reproductive system: Priapism.

Immune system: Skin rashes, conjunctivitis, lacrimation, rhinitis, bronchospasm, asthma, tachypnea, cyanosis, allergic vasospasm in limbs, anaphylactoid reactions, anaphylactic shock.

Endocrine system and metabolism: Hypoaldosteronism, hyperkalemia, increased thyroxine levels, decreased cholesterol levels, elevated blood glucose levels.

Cardiovascular system: Bleeding and hematomas in any organ or organ system (subcutaneous, intramuscular, retroperitoneal, nasal, intestinal, gastric, uterine).

Injection site reactions: Irritation, ulcers, pain, hemorrhage, hematoma, and atrophy at injection sites.

Other: Rhinitis, fever.

Thrombocytopenia as a complication of heparin therapy occurs in 6% of patients. It may arise either as a direct result of platelet aggregation induced by heparin or due to an immune response in which antibodies target platelets and endothelium. First-type reactions are usually mild and resolve after discontinuation of therapy, whereas second-type reactions are severe. As a consequence of thrombocytopenia, skin necrosis and arterial thrombosis ("white clot") may develop, accompanied by recurrent venous thromboembolism, gangrene, myocardial infarction, and stroke. Heparin therapy must be discontinued upon development of severe thrombocytopenia (a decrease in platelet count by half from the initial level).

Elevated transaminase activity (ALT and AST), increased levels of free fatty acids and thyroxine, and reversible potassium retention may also occur.

Shelf life. 3 years.

Storage conditions.

Store out of reach of children.

Store in the original packaging at a temperature not exceeding 25 °C.

Incompatibilities.

Heparin-Farmeks should not be mixed with other medicinal products in the same infusion container or syringe due to the possibility of precipitation.

Dobutamine hydrochloride and heparin must not be mixed or administered intravenously together, as chelate complexes form.

Packaging.

1 ml or 5 ml in vials, 5 vials in a blister pack. 1 blister pack per cardboard box.

Prescription category. Prescription only.

Manufacturer.

LLC "FARMEKS GROUP".

Manufacturer's address and location of operations.

100 Shevchenko Street, Boryspil, Kyiv Oblast, 08301, Ukraine.